1. Field of the Invention
This invention relates to controlled release, drug-delivery systems, and, more particularly, to a tablet composition including a polymer of a vinyl amide, such as vinyl pyrrolidone or N-vinyl formamide, and (meth)acrylic acid, a long chain alkyl (meth)acrylate, and a lower alkyl (meth)acrylate, for effecting the desired controlled release of pharmaceutical medicaments.
2. Description of the Prior Art
In the pharmaceutical industry much work has been devoted during recent years to improving the effectiveness, safety and practicality of orally administered drugs. This invention is specifically directed toward the goal of prolonging the release of an orally taken drug over a period of several hours. Such a prolonged release has the following advantages: peak blood levels of the drug which sometimes represent toxic levels are avoided since not all the drug is released into the stomach at the same time; secondly, drug concentrations in the blood are maintained for a longer time within the therapeutic range, thereby increasing the overall effectiveness of the drug and reducing the overall dose-size necessary for treatment; thirdly, drugs which would have to be taken in conventional form several times daily for the treatment of chronic diseases, can be administered in once or twice-a-day dose forms, which are safer and more convenient for the patient.
Conventional dose forms of orally taken drugs are tablets or pills in which the drug is compounded with a water soluble gum or polysaccharide which quickly dissolves or disintegrates in the stomach. However, tablet disintegration ordinarily is fast and poorly reproducible since it is to a large degree a function of physical motion in the stomach. Therefore, polymeric dosage forms were developed in which the drug-release is diffusion-controlled, independent of physical variables other than polymer compositions and morphology. In these dosage forms the polymer is passed through the body without degradation.
Examples of such a monolithic dose form with uniform drug concentrations are described in Australian Patent No. 16202, and in U.S. Pat. No. 3,390,050, wherein hydrophilic polymer beads are synthesized in the presence of a drug. U.S. Pat. No. 4,267,138 describes an oral dose form in which the release of an active ingredient is controlled by a coating surrounding drug containing particles, which are compressed into tablets. The coatings are complicated mixtures of plasticized synthetic polymers and water.
Australian Patent No. 16202 describes the use of a water swellable poly(2-hydroxyethyl methacrylate) or copolymers of 2-hydroxyethyl methacrylate to imbibe drugs from an aqueous solution. The dried polymer-drug composite forms a controlled oral release device. A similar approach, but using water-swellable polymers (hydrogels) which are themselves two-phase polymers and which exhibit a much wider range of swelling in water and organic solvents is described in U.S. Pat. Nos. 4,192,827 and 4,136,250.
In these hydrogel drug-carriers, the limited swelling ability of the hydrogels limits the amount of drug which can be imbibed into them from a drug solution, be it aqueous or organic in nature. If the polymer swells to a larger degree in a suitable organic solvent than in water, then higher drug-loadings can be achieved by loading from, for instance, ethanol/drug solutions than from aqueous solutions provided the drug is soluble in ethanol. The use of organic solvents to imbibe hydrogels with a drug for later release has also been described in U.S. Pat. No. 4,192,827.
Another hydrogel system for controlled release drug-delivery are described in U.S. Pat. Nos. 4,548,990 and 5,252,611.
U.K. Patent Application GB 2,249,957A, May 27, 1992 describes a controlled release composition comprising an extruded core of active material and excipients, the core being coated in a water-insoluble coating.
U.S. Pat. No. 5,206,386, describes a controlled release composition including N-substituted pyrrolidone esters.
U.S. Pat. No. 4,548,990 describes a controlled-release, drug delivery composition comprising an effective amount of a pharmaceutical medicament in a polymer substrate which can swell in polar organic solvents to a much greater degree than conventional polymers used for drug-delivery and which therefore can be imbibed with active ingredients to a correspondingly high concentration while at the same time exhibiting only a moderate degree of swelling in water.
The ability of a polymer to absorb a large amount of water has always been considered a necessity for a polymeric orally used drug-delivery matrix. Hydrogels have therefore been the only materials previously used for this purpose. Drug diffusion through hydrophobic polymer is normally too slow to be of practical use in an oral drug-delivery. It is consistent with this explanation that hydrophobic polymer-medicament compositions have been used only as body implants where drug delivery over several weeks or even months is desired and where the overall dose size is very low, as is the case, for instance, with steroids.
Accordingly, it is an object of this invention to provide a controlled-release, drug-delivery tablet composition comprising an effective amount of a pharmaceutical medicament in a polymer substrate.